Systemic cells influence hemostasis via several functionally interrelated processes. They synthesize tissue factor (thromboplastin), the initiator of the extrinsic coagulation system and plasminogen activator, an initiator of fibrinolysis. Tissue culture techniques now allow the propagation of isolated cultures of human cells including umbilical vein endothelial and smooth muscle cells. Using fibroblasts in culture we have preliminary evidence that platelet phospholipids/proteolipid fractions can increase the cellular thrombogenicity by increasing tissue factor activity and decreasing apparent fibrinolytic activity; the latter is the result of enhancing expression of a cell-derived plasmin inhibitor. Studies are proposed to further characterize the active moiety in platelets. Our observation that these hemostatic activities vary in a concerted manner suggest that reciprocal control processes for these competing systems may exist at the cellular level. Studies from our laboratory, and also taken from the literature, are consistent with phospholipase A playing a central role in this process. For example, we find dexamethasone, mepacrine and bromphenacyl bromide, all phospholipase A inhibitors, inhibit the phorbol ester-stimulated increase in fibrinolytic activity. The hypothesis that phospholipase A has a central role in reciprocal cellular control processes which determine the level of these hemostatic activities will be tested. Cell-derived inhibitors of both of these systems have now been identified. We have preliminary evidence that a previously undescribed cell-derived thrombin inhibitor exists. While fibrinolytic inhibitors have been known for a number of years, their major contribution to the apparent level of cellular fibrinolytic activity is just becoming appreciated. For example, we find the previously reported dexamethasone-induced decline in fibrinolytic activity is due to elevated levels of plasminogen activator inhibitor. We propose to refine available assay procedures to separate and measure both the initiators and inhibitors of these processes. Finally, functional and structural parameters of the cell-derived inhibitors are unknown and will be studied.